Enforced expression of HOXB4 in human embryonic stem cells enhances the production of hematopoietic progenitors but has no effect on the maturation of red blood cells

Jackson, M. et al. (2016) Enforced expression of HOXB4 in human embryonic stem cells enhances the production of hematopoietic progenitors but has no effect on the maturation of red blood cells. Stem Cells Translational Medicine, 5(8), pp. 981-990. (doi: 10.5966/sctm.2015-0324) (PMID:27352929)

Abstract

We have developed a robust, Good Manufacturing Practice-compatible differentiation protocol capable of producing scalable quantities of red blood cells (RBCs) from human pluripotent stem cells (hPSCs). However, translation of this protocol to the clinic has been compromised because the RBCs produced are not fully mature; thus, they express embryonic and fetal, rather than adult globins, and they do not enucleate efficiently. Based on previous studies, we predicted that activation of exogenous HOXB4 would increase the production of hematopoietic progenitor cells (HPCs) from hPSCs and hypothesized that it might also promote the production of more mature, definitive RBCs. Using a tamoxifen-inducible HOXB4-ERT2 expression system, we first demonstrated that activation of HOXB4 does increase the production of HPCs from hPSCs as determined by colony-forming unit culture activity and the presence of CD43+CD34+ progenitors. Activation of HOXB4 caused a modest, but significant, increase in the proportion of immature CD235a+/CD71+ erythroid cells. However, this did not result in a significant increase in more mature CD235a+/CD71− cells. RBCs produced in the presence of enhanced HOXB4 activity expressed embryonic (ε) and fetal (γ) but not adult (β) globins, and the proportion of enucleated cells was comparable to that of the control cultures. We conclude that programming with the transcription factor HOXB4 increases the production of hematopoietic progenitors and immature erythroid cells but does not resolve the inherent challenges associated with the production of mature adult-like enucleated RBCs.

• Item Type: Articles
• Additional Information: The authors thank the following funding agencies: Wellcome Trust, Scottish Funding Council, the Australian Stem Cell Centre, Stem Cells Australia, the National Health and Medical Research Council (NHMRC) of Australia, and the Victorian Government’s Operational Infrastructure Support program.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mountford, Dr Joanne and Olivier, Dr Emmanuel and Marenah, Dr Lamin
• Authors: Jackson, M., Ma, R., Taylor, A. H., Axton, R. A., Easterbrook, J., Kydonaki, M., Olivier, E., Marenah, L., Stanley, E. G., Elefanty, A. G., Mountford, J. C., and Forrester, L. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Stem Cells Translational Medicine
• Publisher: AlphaMed Press
• ISSN: 2157-6564
• ISSN (Online): 2157-6580
• Published Online: 28 June 2016
• Copyright Holders: Copyright © 2016 AlphaMed Press
• First Published: First published in Stem Cells Translational Medicine 5(8): 981-990
• Publisher Policy: Reproduced in accordance with the publisher copyright policy